Eptifibatide is a highly specific cyclic heptapeptide antagonist of the platelet glycoprotein IIb/IIIa. It is a short-acting parenteral antithrombotic agent that is used during percutaneous coronary interventions for the treatment of unstable angina and as an adjunct to thrombolytic agents for the treatment of acute myocardial infarction. See, for example, Phillips et al., Journal of Biological Chemistry (1993), 268(2), 1066-73; and Scarborough, American Heart Journal (1999), 138(6, Pt. 1), 1093-1104. Eptifibatide is also administered to patients undergoing balloon angioplasty, a procedure for which over 1.0 million people in the U.S. are candidates annually.
Eptifibatide is believed to work by inhibiting platelet aggregation, specifically, by blocking the platelet receptor GP IIb-IIIa. The aggregation of platelets can obstruct blood supply to the heart, causing unstable angina and, possibly, myocardial infarction (heart attack). The effects of eptifibatide are specific to platelets, avoiding interference with other normal cardiovascular processes, and the effects can be reversed when eptifibatide use is discontinued.
Eptifibatide is marketed in the U.S. under the trademark INTEGRILIN®, and is used to treat patients with acute coronary syndrome (unstable angina and non-Q-wave MI), including patients who are to be managed medically and those undergoing percutaneous coronary intervention (“PCI”). Eptifibatide is also indicated for use at the time of percutaneous coronary interventions, including procedures involving intracoronary stenting.
Many reported synthetic approaches to eptifibatide have employed known techniques of solid-phase peptide synthesis as described, for example, in U.S. Pat. Nos. 5,318,899; 5,686,570 and 5,747,447. A commercial-scale, liquid phase process was also reported at the 1999 IBC Conference on Peptide Technologies, “Peptisyntha's Method of Producing GMP Peptides on an Industrial Scale”. The commercial process is a convergent synthesis involving the separate preparation of two fragments: Mpa-Har-Gly and Asp-Trp-Pro. The coupling of these two fragments provides six of the seven residues needed for eptifibatide. The last residue attached is an S-trityl-protected cysteinamide as described, for example, in U.S. Pat. No. 5,506,362. After removal of the S-trityl protecting groups (on the cysteinamide and mercaptopropionyl residues), ring closure is then achieved by disulfide bond formation. Crude eptifibatide obtained by the commercial process has a reported purity of about 80%. Two column chromatography steps improve the purity to greater than 99%.
Liquid-phase synthesis has generally been viewed as more feasible than solid-phase synthesis for the large-scale manufacture of eptifibatide. However, solubility issues and the generation of complex reaction mixtures present challenges for large-scale liquid phase processes. Complex reaction mixtures, for example, make purification of the product more difficult. Ways exist to overcome these problems, such as the use of persilylated amino acids and phase transfer reagents, as described, for example, in U.S. Pat. No. 4,954,616, and extensive chromatographic purification, but such means add to the cost of the overall process.
A need thus exists for alternative processes for the manufacture of eptifibatide.